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991.
四川地区新型抗癫痫药物超说明书规定用药分析:一项对儿童患者的多中心调查研究 总被引:1,自引:0,他引:1
目的调查四川地区左乙拉西坦、托吡酯、奥卡西平和拉莫三嗪等新型抗癫癎药物在儿童癫癎患者中超说明书规定用药(超说明书用药)的现状及安全性,以为临床制定相关用药指南提供数据,并为临床用药提供参考。方法收集2010年7月-2011年11月于四川大学华西第二医院、成都市妇女儿童中心医院和四川省人民医院门诊接受抗癫癎药物治疗的儿童癫癎患者资料,统计此间应用抗癫癎药物的总病例数和服用4种新型抗癫癎药物的病例数。依据药品说明书适应证,判断使用新型抗癫癎药物的医嘱是否属于超说明书用药及其药物类型,并计算和分析超说明书用药发生率及药物不良反应。结果共854例癫癎患儿接受抗癫癎药物治疗,其中670例患儿服用4种新型抗癫癎药物中的一种或多种,超说明书用药者406例,占抗癫癎药物治疗总病例数的47.54%(406/854),约占新型抗癫癎药物治疗总病例数的60.60%(406/670)。与按说明书用药患儿相比,超说明书用药患儿年龄更小、单药使用比例更高、全面性发作和癫癎综合征患儿比例更高,其病例数比例分别为左乙拉西坦78.50%(157/200)、托吡酯79.81%(253/317)、奥卡西平21.32%(42/197)和拉莫三嗪33.33%(21/63);不同年龄、单药使用和各种发作类型中以左乙拉西坦和托吡酯超说明书用药现象更为突出。除失访病例外,超说明书用药组患儿以奥卡西平[16.67%(7/42)]不良反应发生率最高,其次分别为托吡酯[14.81%(36/243)]、左乙拉西坦[10.60%(16/151)]和拉莫三嗪[9.52%(2/21)],但是与按说明书用药组之间差异无统计学意义(χ~2=0.375、0.448、0.014、0.109,P=0.540、0.503、0.906、0.742)。结论在四川地区儿童癫癎患者中超说明书应用新型抗癫癎药物的发生率较高,其中以托吡酯和左乙拉西坦尤为突出,但新型抗癫癎药物在一定范围内超说明书用药仍具有较好的安全性和耐受性。 相似文献
992.
目的:对于颜色的整合,至今无法知道究竟是在哪里完成的,甚至至今也没有一种有效的方法来开展研究,为此,尝试运用了一种新的微秒级高精度刺激显示技术,通过被试对同时或以一足够短的时间间隔先后在计算机屏幕上呈现的红、绿图案的观察实验,探讨颜色整合与感觉记忆的相关性。
方法:实验于2007-03-10在中南民族大学脑认知科学研究室完成。选择5名中南民族大学硕士研究生作为受试者,均视力正常或矫正视力正常,自愿参加实验。在第一个实验中,刺激是先后呈现相等时间间隔的红绿图形,要求被试观察自己看到何种颜色。在第二个实验中,刺激是先后呈现图片中左右两侧的不同颜色的图形,要求待被试透过隔板双眼融合时报告融合色。
结果:①实验一结果:当两幅图片的时间间隔为0~16帧(80 ms内),两幅图形可以融合成稳定的颜色;时间间隔在16帧以上时,呈现了2幅独立的图形。②实验二结果:通过刺激物先后呈现在注视点左右的两幅图片,不能融合为稳定的颜色,呈现的像为瞬态的。
结论:①颜色通过对照大脑三个记忆系统对信息的维持时间,确定红绿颜色融合成黄色是在感觉记忆中实现的。②颜色整合发生在双眼驱动细胞之前。③颜色在感觉记忆上整合。 相似文献
993.
994.
Shou-Jie Shen Le-Mei Wang Guo-Mei Gong Yan-Jiao Wang Jin-Yan Liang Jun-Wen Wang 《RSC advances》2022,12(20):12663
An N-addition reaction between imides and propargyl sulfonium salts was developed to afford sulfur-containing N-vinylimides with moderate to excellent yields. Under the activation of NaOAc·3H2O, imides could undergo deprotonation and propargyl sulfonium salts could isomerize to allenic sulfonium salts. The N-nucleophilic attack initiates the reaction and gives the desired products. Various imides, including arylimides, aliphatic imides and N-(arylsulfonyl) alkyl acylamides, and even bioactive saccharin, thalidomide and pomalidomide could provide organosulfur N-vinylimides compounds. The simple, mild and metal-free reaction conditions, the broad scope of substrates, gram-scale synthesis and convenient transformation embody the synthetic superiority of this process.An N-addition reaction between imides and propargyl sulfonium salts was developed to afford sulfur-containing N-vinylimides with moderate to excellent yields. N-vinylimides represent crucial structural motifs due to the importance of these frameworks (Fig. 1), which are the core structure found in biologically active structures,1 functional materials2 and natural products such as the parazoanthines A–E.3 They can also serve as versatile synthetic intermediates in the synthesis of β-2-amino acid derivatives4 and other complex structures.5Open in a separate windowFig. 1Representative functional N-vinylimides scaffolds.Due to the importance of these N-vinylimides frameworks, the growing interest in this featured moiety has catalyzed a recent spurt of attention for methodology appropriate for its construction. Conventionally, protocols for the synthesis of this important substrate class included transition-metal-catalyzed en-imidic C(sp2)–N bond formation reactions of imides with vinyl halides, pseudohalides or alkynes. The main strategies involved Cu-catalyzed Chan–Lam–Evans reactions,6 Ru-catalyzed hydroimidation reaction of imide with alkyne7 and Pd-catalyzed oxidative amination of alkenes.8 In 2021, Sandtorv''s group reported Cu-catalyzed Chan–Lam–Evans reaction for coupling cyclic imides and alkenylboronic acids by forming C(sp2)–N-bonds, enables the practical and mild preparation of (E)-enimides (Scheme 1a).6a In 2020, Schaub''s group reported Ru-phosphine catalyzed hydroimidation reaction of cyclic amides with acetylene under low pressure, affording new method for synthesis of N-vinylimides (Scheme 1b).7a Hull''s group reported Pd-catalyzed anti-Markovnikov oxidative amination reaction, alkenes are shown to react with imides in the presence of a palladate catalyst to generate the terminal imide, providing mild and robust complementary routes (Scheme 1c).8a Besides, rarely examples of organo-catalytic conjugate additions of imides to acetylene can also provide methods for the synthesis of N-vinylimides.9Open in a separate windowScheme 1Approaches for vinylation of imides.The previously reported synthesis strategies mainly involved the use of expensive Ru and Pd-catalysts, otherwise toxic copper catalyst, and the structural limitations imposed to phthalimide and therefore specialized. Considering the limitation in generality, the harsh reaction condition, and the use of metal-catalysis decreased the attractiveness for synthetic applications, the development of new kind of vinylation reagents and their application of building N-vinylimides in a simple, mild, metal-free and efficient manner are highly desirable.Our earlier work inspired our interest in synthesis of N-vinylimides by employing propargyl sulfonium salts as vinylation reagent. We have been exploring new reaction patterns of sulfonium salts and developed propargyl sulfonium salts involved [3 + 2] annulation/substitution reaction and N-addition/[2,3]-sigmatropic rearrangement reaction in an acyclic model.10 Based on our processive interests on constructing N-functionalized vinylation reaction and exploring the diverse reactive pathway of propargyl sulfonium salts, we herein report the realization of inorganic base promoted N-addition reaction of imides and propargyl sulfonium salts, delivering potential bioactive sulfur-containing N-vinylimides in moderate to excellent yields (Scheme 1).We began our investigation by selecting phthalimide 1a and propargyl sulfonium salt 2a as model substrates (†).Optimization of the reaction conditionsa
Open in a separate windowaUnless otherwise noted, the reactions were performed under air and imide 1a (0.3 mmol, 1.0 equiv.), base (0.45 mmol, 1.5 equiv.) in solvent (3.0 mL, c = 0.1 M) were mixed, the reaction mixture was stirred for 10 min at 22 °C. Then propargyl sulfonium salt 2a (0.45 mmol, 1.5 equiv.) was added in one portion. The reaction was stirred at 50 °C for 6 h until starting material 1a was fully consumed (monitored by TLC).bIsolated yield. DCE: 1,2-dichloroethane; DCM: dichloromethane.cWith the ratio of 1a : 2a : NaOAc·3H2O = 1 : 1.5 : 1.5.Having established the optimized conditions, we commenced to explore the substrate scope of the reaction. A selection of arylimides and aliphatic imides was next investigated with propargyl sulfonium salt 2a in Scheme 2. Generally, arylimides containing electron-withdrawing group such as tetrachloro-, 4-bromo-, 4-nitro- and 3-nitrophthalimide provided desired N-vinylimides products 3b–3e with moderate yields (Scheme 2, 3b–3e, with yields of 27–52%), probably due to the electron withdrawing effect of substituents. 1,8-Naphthalimide and 2,3-naphthalimide were well-tolerated to provide N-vinylimide products 3f and 3g with 62 and 65% yields, respectively. 3,4-Pyridinedicarboximide could also be engaged in the reaction to obtain 3h with yield of 43%. Subsequently, we went on to evaluate the reactivity of aliphatic imides. Unexpected, maleimide could not provide the desired N-nucleophilic addition product under the optimized conditions with recovering of the starting material. Oppositely, the method was high yielding and tolerable to succinimide and substituted succinimides. Succinimide and substituted succinimides worked well to deliver N-vinylimides products 3j–3o with moderate to excellent yields of 52–93%.11 Continuously, we evaluated the reactive effectiveness of glutarimide and substituted glutarimides. Under optimized conditions, glutarimide and substituted glutarimides could also react with 2a and give desired products 3p, 3q and 3r with yields of 32, 24 and 24%, respectively.Open in a separate windowScheme 2Scope of imidesa. aUnless otherwise noted, the reactions were performed under air and imide 1 (0.3 mmol, 1.0 equiv.), NaOAc·3H2O (0.45 mmol, 1.5 equiv.) in CH3CN (3.0 mL, c = 0.1 M) were mixed, the reaction mixture was stirred for 10 min at 22 °C. Then propargyl sulfonium salt 2a (0.45 mmol, 1.5 equiv.) was added in one portion. The reaction was stirred at 50 °C for 6 h until starting material 1 was fully consumed (monitored by TLC). bIsolated yield.Surprising reaction appeared when we explored the reaction of tetrahydro-1H-4,7-epoxyisoindole-1,3(2H)-dione 1s and 1t (Scheme 3).12 Under the optimized conditions, 1s worked well with propargyl sulfonium salt 2a to deliver the corresponding product 3s with yield of 65%. Under the same conditions, compound 1t gave the desired N-vinylimide product 3t with yield of 35%, meanwhile with the unexpected N-vinylimide product 3i with yield of 16%, which unavailable in the reaction of maleimide with propargyl sulfonium salt 2a, probably due to the retro-Diels–Alder reaction of 1t with generation of maleimide intermediate.Open in a separate windowScheme 3Scope of imides.The reaction performance could also be adapted to N-(arylsulfonyl) alkyl acylamides (Scheme 4). The method smoothly transferred electron-deficient aryl sulfonyl acylamides to form N-vinylimide products such as 5a–5e in moderate yields. In contrast, when N-(arylsulfonyl) aryl acylamides 5i and N-(arylacyl) alkyl acylamides 5j–5l were involved, the reaction was sluggish and no desired N-vinylimide products could be obtained probably due to its low nucleophilicity (Scheme 4, 5i–5l).Open in a separate windowScheme 4Scope of aryl sulfonyl amides and carbonimidesa, aUnless otherwise noted, the reactions were performed under air and imide 4 (0.3 mmol, 1.0 equiv.), NaOAc·3H2O (0.45 mmol, 1.5 equiv.) in CH3CN (3.0 mL, c = 0.1 M) were mixed, the reaction mixture was stirred for 10 min at 22 °C. Then propargyl sulfonium salt 2a (0.45 mmol, 1.5 equiv.) was added in one portion. The reaction was stirred at 50 °C for 6 h until starting material 4 was fully consumed (monitored by TLC). bIsolated yield.To further broaden the scope of the reaction, other representative propargyl sulfonium salts were also investigated (Scheme 5). Trimethylsilyl contained propargyl sulfonium salt 2b could be applied to the reaction and the desilylation product 3a was obtained with a yield of 63%. The method was high yielding and tolerable to diverse bioactive molecules, such as saccharin, thalidomide and pomalidomide. Saccharin derivatives have been reported as good hCAs inhibitors,13 and thalidomide and pomalidomide belongs to an important class of molecules known as immunomodulatory imide drugs (IMiDs).14 We found that under optimized conditions, saccharin, thalidomide and pomalidomide were also compatible with propargyl sulfonium salt 2a and provided the corresponding products 7, 9 and 11 with 52, 87, and 80% yields, respectively (Scheme 5).Open in a separate windowScheme 5Scope of propargyl sulfonium salts and bioactive molecules.To demonstrate the synthetic utility of this protocol, we performed the gram-scale operation using phthalimide 1a (1.01 g, 6.8 mmol) and propargyl sulfonium salt 2a (1.5 equiv.) as the representative substrates under the optimized conditions, providing the related product 3a (1.03 g) with 65% yield (Scheme 6). The typical transformation was also conducted by oxidation of compound 3a with m-chloro peroxybenzoic acid (3.0 equiv.) and sulfonyl product 12 was obtained with 94% yield.Open in a separate windowScheme 6Gram-scale synthesis and further transformation.According to the previous reports on α-alkylidene pyrazolinones and propargyl sulfonium ylides,10b,c a possible mechanism is proposed to account for the formation of N-vinylimides 3 (Scheme 7). Under the activation of inorganic base NaOAc·3H2O, the imides 1 may undergo deprotonation to form intermediate I and propargyl sulfonium salt 2a can isomerize to allenic sulfonium salts II. The N-nucleophilic attack of I to allenic sulfonium salts II initiates the reaction and gives intermediate III. Subsequently, protonation of the species III and release of MeBr provided the desired product 3.Open in a separate windowScheme 7Plausible reaction mechanism.In summary, we have developed NaOAc·3H2O promoted N-addition reaction between imides and propargyl sulfonium salts, delivering potentially bioactive N-vinylimides in moderate to excellent yields. Various imides, including arylimides, aliphatic imides and N-(arylsulfonyl) alkyl acylamides, even bioactive saccharin, thalidomide and pomalidomide could tolerate and function to provide organosulfur N-vinylimides compounds. Gram-scale synthesis and convenient transformations are also furnished. The simple, mild, metal-free and efficient reaction condition, the broad scope of substrates, gram-scale synthesis and convenient transformation embody the synthetic superiority of this reaction process. 相似文献
Entry | Base | Solvent | Temp. (°C) | Yieldb (%) |
---|---|---|---|---|
1 | NaOAc | CH3CN | 50 | 45 |
2 | Na2CO3 | CH3CN | 50 | 42 |
3 | K2CO3 | CH3CN | 50 | 46 |
4 | Cs2CO3 | CH3CN | 50 | 39 |
5 | KOH | CH3CN | 50 | 24 |
6 | LiOAc·2H2O | CH3CN | 50 | 33 |
7 | LiOAc | CH3CN | 50 | 42 |
8 | NaH | CH3CN | 50 | 40 |
9 | KOtBu | CH3CN | 50 | 37 |
10 | Et3N | CH3CN | 50 | 36 |
11 | DBU | CH3CN | 50 | 33 |
12 | NaOAc·3H2O | THF | 50 | 37 |
13 | NaOAc·3H2O | CHCl3 | 50 | 34 |
14 | NaOAc·3H2O | DCE | 50 | 28 |
15 | NaOAc·3H2O | DCM | 50 | 35 |
16 | NaOAc·3H2O | Toluene | 50 | Trace |
17c | NaOAc·3H2O | CH3CN | 22 | 11 |
18c | NaOAc·3H2O | CH3CN | 30 | 23 |
19c | NaOAc·3H2O | CH3CN | 60 | 61 |
20c | NaOAc·3H2O | CH3CN | 80 | 51 |
21c | NaOAc·3H2O | CH3CN | 90 | 49 |
995.
Xin-li Liang Miao-miao Ji Zheng-gen Liao Guo-wei Zhao Xi-lan Tang Wei Dong 《The Korean journal of physiology & pharmacology》2022,26(3):145
Multidrug resistance of tumors has been a severe obstacle to the success of cancer chemotherapy. The study wants to investigate the reversal effects of imperatorin (IMP) on doxorubicin (DOX) resistance in K562/DOX leukemia cells, A2780/Taxol cells and in NOD/SCID mice, to explore the possible molecular mechanisms. K562/DOX and A2780/Taxol cells were treated with various concentrations of DOX and Taol with or without different concentrations of IMP, respectively. K562/DOX xenograft model was used to assess anti-tumor effect of IMP combined with DOX. MTT assay, Rhodamine 123 efflux assay, RT-PCR, and Western blot analysis were determined in vivo and in vitro. Results showed that IMP significantly enhanced the cytotoxicity of DOX and Taxol toward corresponding resistance cells. In vivo results illustrated both the tumor volume and tumor weight were significantly decreased after 2-week treatment with IMP combined with DOX compared to the DOX alone group. Western blotting and RT-PCR analyses indicated that IMP downregulated the expression of P-gp in K562/DOX xenograft tumors in NOD/SCID mice. We also evaluated glycolysis and glutamine metabolism in K562/DOX cells by measuring glucose consumption and lactate production. The results revealed that IMP could significantly reduce the glucose consumption and lactate production of K562/DOX cells. Furthermore, IMP could also remarkably repress the glutamine consumption, α-KG and ATP production of K562/DOX cells. Thus, IMP may sensitize K562/DOX cells to DOX and enhance the anti-tumor effect of DOX in K562/DOX xenograft tumors in NOD/SCID mice. IMP may be an adjuvant therapy to mitigate the multidrug resistance in leukemia chemotherapy. 相似文献
996.
目的 探讨针刺通过调节DKK1通路调控骨代谢对于去卵巢模型大鼠(ovariectomized rats,OVX)骨质疏松的影响及其机制.方法 采用经典的双侧卵巢切除进行雌性SD大鼠的原发性骨质疏松造模,阿伦磷酸盐阳性药物对照组服用阿伦磷酸盐治疗,各期针灸组采取针刺双侧"肾腧"穴.观察针刺治疗对OVX大鼠全身骨量、生物力... 相似文献
997.
998.
目的:探讨在高原服用富氧水对移居青年心肺功能的影响。方法:对进驻海拔3700m1年的10名青年在服用富氧水前和服用富氧水(每次500mL,一日2次)15天后分别用EGM-II型踏车功量计做坐位踏车运动,初始负荷功率为50W,每3min递增50W,以60r/min连续踏车至200W,3min后终止。用直线回归法计算每位受试者功率200W时的心率(HR)及血氧饱和度(SaO2),记录运动终止5min后恢复HR,按公式计算心功能指数。结果:服用富氧水15天后,心功能指数增高,功率200W时SaO2增高;功率200W时的HR和运动终止5min恢复HR降低,差别有非常显著性意义(P〈0.01)。结论:服用富氧水能提高高原移居青年的心肺功能。 相似文献
999.
目的探讨肝癌肝移植方法,并评价其疗效,以提高肝癌救治成功率。方法回顾2003年9月以来本院17例肝癌肝移植诊治过程,总结治疗过程中的成功经验和教训。结果17例肝移植病人围手术期均顺利恢复,全部获得随访,随访时间:3~19个月;14例存活,3例死亡,此3例分别于术后4个月、7个月、9个月因肺和(或)肝转移死亡外,14例均存活中带癌生存3例,1年以上6例,6~12个月5例,3~6个月3例。结论肝癌是肝移植相对适应证,是一种疗效肯定的治疗方法,规范围手术期处理方法,并进行术后合理治疗,部分病人可获长期生存。 相似文献
1000.
目的 探讨高速三角破片致猪坐骨神经损伤的伤情特点. 方法 长白猪14只,体重(34.3±5.2)kg.采用随机数字表法分为A、B两组各7只,用初速为(773.1±12.4)m/s的0.37 g三角破片致伤,分别瞄准猪右后肢外侧坐骨神经体表投影线中点和旁开2 cm射击.观察伤道入口和出口大小、长度,神经与伤道位置关系,伤后48 h观察神经大体及光电镜改变. 结果 破片在伤道内存在不同程度的偏离原射入方向.A、B组分别有5只和1只坐骨神经位于原发伤道内,其中4例出现不间程度断裂;光镜下见神经严重出血水肿、炎细胞浸润,大量神经纤维、轴索断裂,髓鞘着色浅;电镜下见髓鞘严重溃变、轴索变形.A、B组分别有1只和5只位于震荡区内,距原发伤道(2.07±0.45)cm,光镜见神经轻度出血、充血,部分神经纤维、轴索断裂;电镜下可见髓鞘部分分层.A、B组各有1只位于挫伤区内,神经受损程度介于二者之间. 结论 高速三角破片在组织内走行不稳定;其原发伤道内的猪坐骨神经断裂发牛率高,损伤严重,范围广,华勒变性早;位于原发伤道旁的神经亦发生形态学改变,其损害程度与神经和原发伤道距离有关. 相似文献